Most cases of genital herpes are due to herpes simplex virus (HSV)-2. The rate of HSV-2 infections increased by 30% from 1988 to 1994. In addition to genital herpes, transmission of HSV-2 to neonates causes severe life-threatening infections. Recent studies demonstrate a link between genital herpes and increased rates of transmission of HIV and elevated levels of HIV in the blood. HIV causes a number of opportunistic infections and is associated with increased rates of several cancers including lymphomas. Therefore, an effective HSV-2 vaccine is needed. Several HSV-2 vaccines have tested in humans for prevention or reduction genital herpes disease. A vaccine containing a single viral protein (HSV-2 glycoprotein D) reduced the rate of HSV-2 disease in women who were not previously infected with HSV-1 in two randomized, controlled clinical trials. The HSV-2 glycoprotein D vaccine, however, showed no efficacy in women previously infected with HSV-1 or in men. We postulated that the limited efficacy of the HSV-2 glycoprotein D vaccine is likely due to inadequate induction of cellular immune responses. We have been evaluating a candidate HSV-2 vaccine deleted for two essential genes, termed HSV-2 dl5-29, which was developed by David Knipe at Harvard University. As noted above, while an HSV-2 candidate vaccine consisting of glycoprotein D (gD2) in alum and monophosphoryl lipid A (MPL) reduced genital herpes disease in HSV-1 seronegative women, it was not effective in men or HSV-1 seropositive women. This year, we compared the ability of dl5-29 versus gD2 in alum/MPL to protect guinea pigs from HSV-2 infection. In HSV-1 seronegative animals, dl5-29 induced higher titers of neutralizing antibody, and after vaginal challenge with wild-type virus, dl5-29 resulted in lower rates of vaginal shedding, lower levels of HSV DNA in ganglia, and a trend for less acute and recurrent genital herpes than the gD2 vaccine. In HSV-1 seropositive animals, all three vaccines induced similar titers of neutralizing antibodies and showed similar levels of protection against acute and recurrent genital herpes after vaginal challenge with wild-type virus, but dl5-29 reduced vaginal shedding after challenge more than the gD2 vaccine. Thus, dl5-29 was an effective vaccine in both HSV-1 seropositive and seronegative guinea pigs, and was superior to the gD2 vaccine in reducing virus shedding after challenge in both groups of animals and therefore might help to reduce transmission of HSV-2.